Empirical valence bond simulations of the hydride transfer step in the monoamine oxidase B catalyzed metabolism of dopamine

Abstract

Monoamine oxidases (MAOs) A and B are flavoenzymes responsible for the metabolism of biogenic amines such as dopamine, serotonin and noradrenaline. In this work, we present a comprehensive study of the rate-limiting step of dopamine degradation by MAO B, which consists in the hydride transfer from the methylene group of the substrate to the flavin moiety of the FAD prosthetic group. This article builds on our previous quantum chemical study of the same reaction using a cluster model (Vianello et al., Eur J Org Chem 2012; 7057), but now considering the full dimensionality of the hydrated enzyme with extensive configurational sampling. We show that MAO B is specifically tuned to catalyze the hydride transfer step from the substrate to the flavin moiety of the FAD prosthetic group and that it lowers the activation barrier by 12.3 kcal mol⁻¹ compared to the same reaction in aqueous solution, a rate enhancement of more than nine orders of magnitude. Taking into account the deprotonation of the substrate prior to the hydride transfer reaction, the activation barrier in the enzyme is calculated to be 16.1 kcal mol⁻¹, in excellent agreement with the experimental value of 16.5 kcal mol⁻¹. Additionally, we demonstrate that the protonation state of the active site residue Lys296 does not have an influence on the hydride transfer reaction.

Molecular aspects of monoamine oxidase B

“…for formation of the transition state of 16.1 kcal mol -1 (Repic et al, 2014) in excellent agreement with the experimental value of 16.5 kcal mol -1 (Edmondson et al, 2009).…”

“…Using different methods, two computational approaches support either the polar nucleophilic (Abad et al, 2013) or the hydride ion transfer (Vianello et al, 2012, Repic et al, 2014. The hydride ion transfer mechanism gives the lowest activation energy making it the most likely pathway, but better experimental evidence for the transition states for each calculated mechanism would be useful.…”

What a Difference a Methyl Group Makes: The Selectivity of Monoamine Oxidase B Towards Histamine and N‐Methylhistamine

“…[9] This studyw as later extendedb yc onsidering the full enzyme dimensionality through the empiricalv alence bond QM/MM approach( MM = molecular mechanical), which gave the activation free energy of 16.1 kcal mol À1 , [10] being in excellent agreement with the experimentalv alue of 16.5 kcal mol À1 , [11] thuss upporting the proposed hydridet ransferm echanism.O ur mechanistic picture is already gaining some affirmationi nt he literature, [12] and is fully corroborated by av ery recent 13 Ck inetic isotope effect measuremento nar elated polyamine oxidase flavoenzyme. [9] This studyw as later extendedb yc onsidering the full enzyme dimensionality through the empiricalv alence bond QM/MM approach( MM = molecular mechanical), which gave the activation free energy of 16.1 kcal mol À1 , [10] being in excellent agreement with the experimentalv alue of 16.5 kcal mol À1 , [11] thuss upporting the proposed hydridet ransferm echanism.O ur mechanistic picture is already gaining some affirmationi nt he literature, [12] and is fully corroborated by av ery recent 13 Ck inetic isotope effect measuremento nar elated polyamine oxidase flavoenzyme.…”

The Chemistry of Neurodegeneration: Kinetic Data and Their Implications

“…Interestingly, dopaminergic neurons contain more MAO A than MAO B while for serotonergic neurons the opposite is true [94,95]. Recently, we suggested and quantified a novel two-step hydride mechanism of the MAO catalytic reaction [96,97], which should aid in developing more specific and effective inhibitors as transitionstate analogues, acting as anti-depressants and antiparkinsonian drugs. The rate constant for MAO B catalysed dopamine decomposition is around 1 s −1 , which is faster than the metal-free dopamine auto-oxidation (0.43 s −1 ), yet slower than when auto-oxidation is assisted with heavy metal ions (6.75 s −1 ) [53, 98,99].…”